Lipid kinases catalyse the phosphorylation of lipids to produce species involved in the regulation of a wide range of physiological processes, including cellular migration and adhesion. The PI3 kinases (PI3K) are membrane associated proteins and belong to the class of enzymes which catalyse the phosphorylation of lipids which are themselves associated with cell membranes. The PI3K delta isozyme (PI3K δ) is one of four isoforms of type I PI3K kinases responsible for generating various 3′-phosphorylated phosphoinositides, that mediate cellular signalling and have been implicated in inflammation, growth factor signalling, malignant transformation and immunity [See Review by Rameh, L. E. and Cantley, L. C. J. Biol. Chem., 1999, 274:8347-8350.].
The involvement of PI3K in controlling inflammation has been confirmed in several models using pan-active PI3K inhibitors, such as LY-294002 and Wortmannin [Ito, K. et al., J Pharmacol. Exp. Ther., 2007, 321:1-8.]. Recent studies have been conducted using either selective PI3K inhibitors or in knock-out mice lacking a specific enzyme isoform as described below. These studies have demonstrated the role of pathways controlled by PI3K enzymes in inflammation. The PI3K δ selective inhibitor IC-87114 was found to inhibit airways hyper-responsiveness, IgE release, pro-inflammatory cytokine expression, inflammatory cell accumulation into the lung and vascular permeability in ovalbumin-sensitized, ovalbumin-challenged mice [Lee, K. S. et al., J. Allergy Clin. Immunol., 2006, 118:403-409 and Lee, K. S. et al., FASEB J., 2006, 20:455-65.]. In addition, IC-87114 lowered neutrophil accumulation in the lungs of mice and neutrophil function, stimulated by TNFα [Sadhu, C. et al., Biochem. Biophys. Res. Commun., 2003, 308:764-9].
The PI3K δ isoform is activated by insulin and other growth factors, as well as by G-protein coupled protein signaling and inflammatory cytokines. Furthermore, studies using knockout mice revealed that activation of PI3K γ may be important in the pathogenesis of asthma. For example, murine mast cell responses are exacerbated in vitro and in vivo by autocrine signals which require functional PI3K γ. Mice that lacked PI3K γ did not exhibit edema when challenged by passive systemic anaphylaxis [Wymann M. P. et al., Biochem. Soc. Trans., 2003, 31:275-80.]. Thus PI3K γ relays inflammatory signals through various G-protein coupled receptors (GPCRs), especially by controlling mast cell function. Eosinophil accumulation in ovalbumin sensitised and challenged mice was also reported to be inhibited in these PI3K γ-deficient mice, as compared with wild-type animals [Lim D. H. et al., Am. J. Physiol. Lung Cell. Mol. Physiol., 2009, 296(2):L210-L219]. Finally, treatment with a PI3K γ inhibitor attenuated IL-13-augmented airway contractility of lung slices [Jiang H. et al., J. Pharmacol. Exp. Ther., 2012, 342(2):305-11.].
Recently the PI3K dual δ/γ inhibitor TG100-115 was reported to inhibit pulmonary eosinophilia and decrease interleukin-13 levels, mucin accumulation and airways hyper-responsiveness in a murine model, when administered by aerosolisation. The same authors also reported that the compound was able to inhibit pulmonary neutrophilia elicited by either LPS or cigarette smoke [Doukas, J. et al., J Pharmacol. Exp. Ther., 2009, 328:758-765.]. Other small molecule inhibitors of PI3K δ and γ were reported to produce superior inhibition of LPS induced TNFα production and T cell activation when compared with PI3K δ selective inhibitors [Williams O. et al., Chem Biol., 2010, 17(2):123-34.].
Since it is also activated by oxidative stress, the PI3K δ isoform is likely to be relevant as a target for therapeutic intervention in those diseases where a high level of oxidative stress is implicated. Downstream mediators of the PI3K signal transduction pathway include Akt (a serine/threonine protein kinase) and the mammalian target of rapamycin, the enzyme mTOR. Recent work has suggested that activation of PI3K δ, leading to phosphorylation of Akt, is able to induce a state of corticosteroid resistance in otherwise corticosteroid-sensitive cells [To, Y. et al., Am. J. Respir. Crit. Care Med., 2010, 182:897-904.]. These observations have led to the hypothesis that this signalling cascade could be one mechanism responsible for the corticosteroid-insensitivity of inflammation observed in the lungs of patients suffering from COPD, as well as in those asthmatics who smoke, thereby subjecting their lungs to increased oxidative stress. Indeed, theophylline, a compound used in the treatment of both COPD and asthma, has been suggested to reverse steroid insensitivity through mechanisms involving interaction with pathways controlled by PI3 kinase δ [To, Y. et al., Am. J. Respir. Crit. Care Med., 2010, 182:897-904.].
At present the mainstay of treatment for both asthma and COPD is inhaled therapy, using a combination of corticosteroids, muscarinic antagonists and β2-agonists, as judged clinically appropriate. One way of addressing the unmet medical needs in COPD and asthma is to identify new inhaled medicines, which have the potential to provide significant benefit when used either as a monotherapy or in combination with one or more medicaments from these three pharmacological classes. Therefore, there remains a need to identify and develop isoform selective PI3K inhibitors which have the potential to provide enhanced therapeutic efficacy in asthma, COPD and other inflammatory diseases.
WO 2012/052753 discloses: 6-(2-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N,N-bis(2-methoxyethyl)hex-5-ynamide, referred to herein as prior art Compound A.
WO 2011/048111 discloses certain 3-benzyl-5-alkynyl-quinazolin-4(3H)-ones
A compound example disclosed therein is 2-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-fluorobenzyl)-5-(3-(2-(2-methoxyethoxy)ethoxy)prop-1-ynyl)quinazolin-4(3H)-one, referred to herein as Example 50.
Neither of these prior art compounds possess the same advantageous profile of the compound of formula (I) described herein.